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AIDS Treatment News
New Trial Proposed for When Drugs Fail
John S. James
May 19, 1995
AIDS TREATMENT NEWS Issue #223, May 19, 1995

On May 11 this writer and other community representatives met with members of the Clinical Trials subcommittee of the Inter-Company Collaboration for AIDS Drug Development (ICC). The ICC is a group of 17 major pharmaceutical companies which have agreed to share information to facilitate more rapid development of AIDS treatments, especially combination antiretrovirals. The meeting was chaired by David Barry, M.D., who is Group Director of Research and Development for Burroughs Wellcome Co., and chairman of the Clinical Trials subcommittee of the ICC.

Dr. Barry said that the kind of innovative trial design which would get the most support in the ICC today would be studies of combinations of drugs (often entirely new ones) in patients who already have resistant virus. In practice, this will usually mean studies in patients who have already used AZT and/or other antiretrovirals, and for whom the drugs are no longer working well. There are different kinds of laboratory tests to tell if a patients' virus is resistant to certain drugs; patients might be selected based on those tests, or in some cases they might be selected based on clinical failure of the drugs they have been using.

This emphasis on "experienced" patients -- those who have already used AZT or other drugs for some time -- is important for several reasons. First, many of the trials conducted until now have sought "naive" patients as the most desirable -- for example, the only ICC trials proposed so far insist on naive patients. This means that many people who most need a new drug are disqualified from studies (unless they lie), and also that there are large numbers of people for whom new treatments are not being developed.

In addition, it is difficult to recruit naive patients for trials. This problem may seem unexpected, because there are a great many people with HIV who have never used AZT or any other treatment for their condition -- probably many more of them than of those who have received treatment. But usually these people are untreated for a reason. Many do not know they are infected. Others have chosen not to use any of the available drugs, due to concern about side effects, fear of being disqualified for clinical trials for treatment-naive patients in the future, or for other reasons. It is difficult to persuade people who have not wanted conventional treatment in the past to now be willing to enter trials of experimental drugs. By contrast, there are many who are now in the healthcare system who are willing to take drugs and know that they need new ones.

There is also a scientific reason why trials with patients who already have resistant virus are important. Dr. Barry said that by studying them it may be possible to learn much that will apply to naive patients -- but much faster than by studies in the naive patients directly. This could provide what might be called a "surrogate marker" for DURATION of benefit -- a very important indication of drug usefulness which is not otherwise available. [This is possible because patients who have developed resistant virus will have developed a very large number of different "quasispecies" of HIV. If a new drug combination can suppress all of them, well enough to bring the viral load down to about 100 copies per ml or less for at least six months, then that same combination will probably suppress virus for very much longer in naive patients who have not yet build up many resistant or cross-resistant quasispecies.] Dr. Barry suggested a trial design for this purpose. First, before planning the trial in detail, it will be necessary to decide what tests to use to define who has resistant virus; today it is not certain whether "genotypic" tests (which look in the DNA of the virus for a mutation which is known to confer resistance) or "phenotypic" tests (which grow the live virus in the laboratory and see how much drug it can tolerate) would be best for this purpose. Dr. Barry left the question of definition for later.

The kind of trial he proposed could use a very small number of patients (probably well under 30) with resistant virus. These patients could get one of several different drug combination regimens (ideally consisting of new drugs which the patient had never used before). The choice among the several available regimens could be made in several ways: it might depend on which particular mutation the patient had, or it might be random, or it might be the choice of the patient and treating physician, or of the experimenters.

While on the new-drug regimen, both the CD4 (T-helper) count and viral load would be followed. As long as a patient does well -- as long as the viral load remains low and the CD4 count does not decline -- he or she would remain on the treatment. But whoever stops doing well -- whether in six days, six weeks, or six months -- then moves to another of the available regimens.

Dr. Barry believes that if the data is recorded carefully, and if the original resistance is known, then this trial could be of great benefit not only to the patients themselves, but also to others in the future, because it would tell which resistance patterns respond to which drugs.

This design implies that the patients in the trial will have to be treated and followed individually. This is because every patient has a number of different quasispecies of HIV; every patient is different from every other in the collection of quasispecies they have. This means that even if two patients have the same resistance mutation (in some of their quasispecies), and are the same by all other available tests, they may still react very differently to the same drug combination. This individualizing of care makes the trial more in the patient's interest than conventional trials which use standardized treatment protocols to see which does better or worse on the average.

Note also that in this proposed trial, patients and their physicians will receive their viral load, CD4, and other blood work results immediately -- not after the study is over, as in many other trials. They will need to know those results as soon as possible in order to know when it is necessary to change treatments.

Other Proposals Three other proposals were also made at the meeting.

(1) Small, uncontrolled trials. Bill Bahlman, of the Treatment and Data Committee of ACT UP/New York, proposed small, uncontrolled screening trials for initial tests of new combinations.

(An earlier draft of this proposal was published in AIDS TREATMENT NEWS, issue #221, April 21, 1995.) Each trial will have about 30 patients, and will last about six to ten weeks, but with an additional followup phase lasting for at least a year, for those patients who choose to stay on the treatment. Bahlman would study both antiretroviral naive patients with CD4 count above 300, and antiretroviral experienced patients with CD4 under 300. A change from the earlier version of the study is that there will be no requirement that patients have a minimum viral load -- since modern tests can detect very low levels of the virus, even those who start with a low level will still be able to show if they are getting benefit from starting a new treatment regimen.

This proposal is controversial because it does not randomly assign patients to two or more different treatment groups; therefore, when the results are analyzed, there will not be different groups in the same study to compare. But these are preliminary, pilot studies, to quickly screen combinations to see which are worth testing in larger, more formal trials. And these screening studies are looking for large effects, not for small differences. It should be possible to spot combinations which have outstanding short-term antiviral activity in people, by looking for large changes in viral load and CD4 count.

(2) Combining different protease inhibitors. Jules Levin of the New York University Community Advisory Board brought a proposal by two NYU investigators, Roy Gulick, M.D., and Fred Valentine, M.D., to compare MK-639 (the Merck protease inhibitor) alone, vs. saquinavir (the Hoffmann-La Roche protease inhibitor) alone, vs. the two together. This would be a randomized, pilot study with about 90 patients, lasting 24 weeks, in persons with CD4 count 50 to 500 who had not previously used any protease inhibitor. It would look for safety and toxicity, changes in viral load and in CD4, and resistance patterns.

The main point of this proposal was to combine two protease inhibitors; the drugs selected are those which are furthest along in clinical development. Combining protease inhibitors has been suggested, but has not yet been done in trials; the only way for a person to obtain two of the drugs would be to register for different trials under different names, and it is believed that a few people have done so.

Both Merck and Roche representatives said that they have been discussing a combined protease inhibitor trial. But Roche is waiting for its new formulation, which will have about three times greater bioavailability than the current version of saquinavir. When that is available, then there will be a dose-finding study, and then a PK (pharmacokinetic) study to look for interaction between the drugs (there is concern that protease inhibitors might interact with each other in unknown ways, because most of them are metabolized by the liver). Only when these studies are done will the combined trial be run.

An obvious way to speed this process would be to start now and use the existing formulation; when the new one becomes available, switch to it and adjust the dose in the ratio of the average bioavailabilities. Once it reaches the bloodstream, the new formulation is the same drug; the difference is how much of it is absorbed when taken orally. But companies are reluctant to begin a new trial with a substance they expect to abandon, and this strategy for saving time was not discussed at the meeting.

(3) Computerizing medical records. Existing projects are already computerizing medical-record information of HIV patients. But almost all of these are extracting data from existing paper records, then entering it into a database. This approach leads to transcription errors; also, much of the data is never recorded and is lost to research.

Dr. Barry outlined major advantages for research if most HIV physicians would keep their primary patient records by computer, and then share data for research purposes, after names and other identifying information had been removed. For example, it would in theory be possible to find patients who had (secretly) taken more than one protease inhibitor at the same time, and check for any possible side effects which occurred; this information could make future studies safer and faster. Many other drug combinations could be checked in the same way, to look for treatment regimens which might be working unexpectedly well, or unexpectedly poorly.

Confidentiality will be a major concern. It is important to bring all of a patient's records together in the research database; this could be done anonymously, by using a code number, so that the institution holding the combined data would not have the names of patients. But some problems would remain. For example, when a research team studying protease inhibitors looked for the records of all patients taking more than one, they might be able to identify one of their volunteers because some of the blood work would match their records exactly, and then they might no longer want that volunteer in their trial. Unless the system can guarantee that patients will not be harmed by participating, it will be difficult to get their cooperation. And with medical care as fragmented as it is in the U.S., it would be impossible to enforce cooperation effectively, even if this were desired.

Note: Over two years ago AIDS TREATMENT NEWS reported on Medsys, an early system which computerized patients' medical records very effectively, primarily for use within the primary-care office or clinic; physicians could also share the information anonymously for research purposes, if they chose to do so. What impressed us most about this system, developed by a team led by Larry Bruni, M.D., at the National Community Research Initiative in Washington, D.C., was its ease of use; in one afternoon, medical office employees could learn how to use it effectively. But medical-record computerization has not yet caught on in AIDS practices, either public or private.

For background on the NCRI system, see "New Software Available for physicians' Offices and Community-Based Research," AIDS TREATMENT NEWS #165, December 18, 1992. For current information, call Medical Management Systems, 202/546-0887.

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